The overall objective of the proposed research is to elucidate the mechanism whereby various drugs and chemicals interact with the end-plate receptor/channel. In our recent studies, we have found that certain guanidine derivatives such as methylguanidine and amylguanidine block the end-plate in a manner dependent upon the current. Since a variety of guanidine and other ammonium derivatives are available and since the potency spectrum for end-plate block seems to be related to molecular size and specific groups, further exploration of the mechanism of end-plate block by these compounds is expected to provide us with a clearer picture of the end-plate receptor/channel with respect to the pore dimension, gating mechanism and ionic selectivity. In order to accomplish the goal, a vareity of advanced electrophysiological techniques will be employed including voltage clamp, noise analysis and single channel recording. The major goal for the coming year is to perform fluctuation analyses for the action a guanidine derivatives on the end-plate ionic channel. Experiments will also be performed to determine whether the guanidine block is voltage-dependent or current-dependent. The proposed study with neuromuscular junctions will provide us with the basis on which the actions of a variety of pharmacological and therapeutic drugs on synapses in the central nervous system and ganglia can be interpreted. It is also expected that the results will give useful guides for improvements and creation of therapeutic agents on the nervous system.